tbuckley/cabot-search huggingface dataset:
Kidney cancer mortality in the United States between 1999 and 2020: An observational analysis of outcomes by gender, race, and ethnicity.
Authors: Nour Abdallah, Chinmay Jani, Christian Mouchati, Pavlina Chrysafi, Harpreet Singh, Rana R. McKay
Journal: Journal of Clinical Oncology (2023)

4563 Background: Kidney cancer (KC) is one of the leading causes of cancer mortality, with recent data showing an increase in incidence and mortality worldwide. Gender, racial, and ethnic disparities can impact KC outcomes. Studies investigating the outcomes of diverse patient populations spanning the cytokine, targeted therapy and immunotherapy eras have been limited. This study aims to investigate trends in age-adjusted mortality rates (ASMR) by gender, race, and ethnicity in the US at national and state levels. Methods: We utilized the Center for Disease Control Wonder database to extract national and state-wide KC mortality data (ICD-10 C64) from 1999-2020. ASMR and 95% confidence intervals (CI) were extracted based on gender, race and ethnicity reported per 100,000 population. To evaluate the difference between metro and non-metro regions, we divided the national trends based on 2013 Urban NCHS Urban-Rural scheme. Joinpoint regression analysis was performed to evaluate trends. Results: In total, 284,224 KC deaths were reported over twenty years, with an overall decrease in ASMR in recent years. Males had significantly higher ASMR throughout the study period, with a lower decrease than females. Amongst racial groups, American Indians (AI) had the highest mortality in 1999 (5.7). However, due to the smaller decrease of ASMR in Whites compared to Non-Whites, Whites showed the highest ASMR (3.9) in 2020. According to ethnicity, Non-Hispanics Whites (NHW) had significantly higher ASMR than Hispanics in 1999 (4.0 vs. 3.5) and 2020 (3.5 vs. 3.0) with a similar rate of decline (-11.4% vs. -12.5%). State-wise, ASMR decreased in all states except Utah (+45.8%), Arkansas (+18.4%), Hawaii (+15.4%), Montana (+5.3), Kansas (+2.7) and Nevada (+2.6). Interestingly, non-metro regions showed higher ASMR throughout the study period. Also, while there was a steep decline in ASMR (15%) in metro regions, only a minimal decline (-4.7%) was observed in non-metro regions. Conclusions: Over the last two decades, there has been a decrease in the ASMRs across all genders, races and ethnicities and in most states in the USA. The decrease in ASMR is likely multifactorial, related to earlier detection and improved treatments. However, differences in outcomes by gender, race, and ethnicity persist, highlighting the need for strategies to better understand the etiology of differences and mitigate disparities across social determinants of health across gender, racial, and ethnic groups. [Table: see text]
Palbociclib, trastuzumab, pyrotinib and fulvestrant in patients with brain metastasis from ER/PR positive, HER-2 positive breast cancer: Report from an interim analysis of a multicenter, prospective study in China.
Authors: Ruoxi Hong, Fei Xu, Yongkui Lu, Caiwen Du, Zhongyu Yuan, Yanxia Shi, Wen Xia, Shusen Wang
Journal: Journal of Clinical Oncology (2023)

e13032 Background: HER2-positive breast cancer patients are at a high risk of developing metastases in brain. Effective treatment should involve anti-HER2 targeted therapy. This aim of this study is to evaluate the activity of the chemo-free combination of palbociclib, trastuzumab and pyrotinib with fulvestrant in ER positive, HER2-positive breast cancer patients with brain metastasis. Methods: We did a multi-center, prospective trial in three hospitals in China. Female patients older than 18 years who had whole brain radiotherapy-naive ER/PR positive, HER2-positive brain metastases with an Eastern Cooperative Oncology Group performance status of 0–2 were treated with palbociclib, fulvestrant, combined with trastuzumab and pyrotinib, and until disease progression or intolerable adverse effects. The primary endpoint was objective response rate in the central nervous system (CNS), as assessed by investigator per the modified Response Evaluation Criteria In Solid Tumours (version 1.1). The study is still ongoing and recruiting. Here we report the results of an interim analysis. The study is registered with ClinicalTrials.gov, NCT04334330. Results: Between December 4, 2020 and November 2, 2022, 15 patients were enrolled. Eleven patients had prior exposure to trastuzumab. In the 14 patients who were evaluable for clinical response, the objective response rate in the CNS was 28.6%? (95% CI, 8.4% - 58.1%). At a median follow-up of 6.3 months (range, 2.1-14.3 months), the median PFS was 10.6 months (95%CI, 4.3 – 16.9 months). The time to progression in the CNS was 8.5 months (95%CI, 5.9 – 11.1 months). Conclusions: Combination of palbociclib, trastuzumab and pyrotinib with fulvestrant represents an active chemo-free treatment strategy in hormonal receptor positive, HER2-positive breast cancer patients with brain metastasis. Clinical trial information: NCT04334330 .
Gut microbiome composition as predictor of the efficacy of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in metastatic colorectal cancer: A translational analysis of the AtezoTRIBE study.
Authors: Federica Marmorino, Gianmarco Piccinno, Daniele Rossini, Filippo Ghelardi, Sabina Murgioni, Lisa Salvatore, Vincenzo Nasca, Carlotta Antoniotti, Francesca Daniel, Francesco Schietroma, Veronica Conca, Carolina Alves Costa Silva, Emiliano Tamburini, Stefano Tamberi, Alessandro Passardi, Lorenzo Antonuzzo, Raffaella D'Onofrio, Laurence Zitvogel, Chiara Cremolini, Lisa Derosa
Journal: Journal of Clinical Oncology (2023)

3534 Background: Gut microbiome has emerged as a biomarker of clinical benefit to immune-checkpoint inhibitors (ICI) but no data are available in metastatic colorectal cancer (mCRC). The AtezoTRIBE study demonstrated that the addition of atezolizumab (atezo) to FOLFOXIRI plus bevacizumab (bev) prolongs progression-free survival (PFS), but this benefit is limited for patients with proficient mismatch repair (pMMR) tumors. Here, we aimed at investigating the potential predictive role of microbiome in identifying mCRC patients able to achieve benefit from ICI. Methods: AtezoTRIBE was a phase II trial in which 218 mCRC patients, unselected for MMR status, were randomized 1:2 to receive first-line FOLFOXIRI/bev (arm A) or FOLFOXIRI/bev/atezo (arm B). Stools were prospectively collected. Metagenomic (MG) data from whole genome sequencing (WGS) at level of species genome bins (SGBs) were analysed by linear models corrected for clinical and tumor-related parameters and fold-ratios. We defined as responders (R) those patients who experienced a PFS ≥ 12 months. Results: Stool samples were collected at baseline for 171 (78%) patients (55 in arm A and 116 in arm B) but only 163 were available for MG. Patients with deficient MMR (dMMR) tumors (N = 10) showed significantly lower MG diversity than pMMR ones (N = 148) harboring oral bacteria and pathobionts whose intrinsic immunogenicity has not been demonstrated. Regarding pMMR mCRC patients, baseline microbiome composition was not significantly different according to the treatment arm. The microbiome diversity was not significantly different between R and not-R in both arms, but specific immunogenic SGBs (Lachnospiraceae family members) were over-represented in R treated in arm B. Veillonellaceae and pathobionts were associated with poor prognosis and/or differential benefit from the addition of atezo. Fusobacterium nucleatum was associated with a poor prognosis, also in arm B. Conclusions: This is the largest prospective analysis showing that SGBs may be useful as a biomarker of potential benefit or detrimental effect from atezo in pMMR mCRC patients. Our results prompt the design of microbiota-centered diagnostic tests to identify pMMR mCRC patients more likely to benefit from ICI-based therapeutic strategies. Clinical trial information: NCT03721653 .
Medullomyoblastoma: A study of demographic and socioeconomic factors.
Authors: Sagar Patel, Beau Hsia, Darby Keirns, Peter T. Silberstein, Xinxin Wu
Journal: Journal of Clinical Oncology (2023)

e14064 Background: Medullomyoblastoma is a rare cerebellar cancer theorized to be of teratomatous origin and a more aggressive variant of medulloblastoma primarily affecting children under 10 Despite treatment with excision surgery, the survival period is less than 1 year. There is no standard treatment and previous studies have only looked at median follow-up and radiotherapy. A study using National Cancer Database data would be beneficial to examine the impact of demographic factors on risk and treatment. Methods: A retrospective cohort study using data from the National Cancer Database from 2005 to 2019 analyzed 19 patients diagnosed with medullomyoblastoma. The study examined demographic factors such as age, sex, race, Hispanic origin, insurance coverage, distance from facility, and Charlson-Deyo score through descriptive statistics and evaluated trends in incidence through regression analysis. Results: A total of 19 patients were identified in the database with a confirmed diagnosis of medullomyoblastoma between 2005 – 2019, with a slightly declining incidence of patients diagnosed per year (R2 = 0.155). The average age of diagnosis was 13.5 years (SD = 12.5, range = 1 – 44 years), with 52.6% of affected individuals being children under the age of 10. Males and females were affected relatively equally (52.6% and 47.4%, respectively). The top primary site was the cerebellum (84.2%). Most individuals (94.7%) had Charlson-Deyo comorbidity scores of 0. The majority of individuals (68.4%) received treatment as some form of tumor excision surgery (local tumor excision with or without combination of photodynamic therapy, electrocautery, cryosurgery, wide excision, or radical excision). The majority of the patients were non-Hispanic and White (94.7%). A higher percentage of patients were privately insured (68.4%) than those who were uninsured or insured by Medicaid. The majority (84.2%) of patients lived in a metropolitan area. Patients lived an average of 48.6 miles (SD = 57.1, range = 0.6 – 189.5) from the treatment facility. No patients received palliative care. Conclusions: To the best of our knowledge, this is the first NCDB study on medullomyoblastoma, filling a crucial gap in knowledge. Results show the majority of patients are non-Hispanic White children, with primary site at the cerebellum, similar to previous case reports. For the first time, socioeconomic characteristics of medullomyoblastoma patients have been documented, such as the majority of patients being privately insured living in metropolitan areas. Treatment-wise, patients receive tumor excision surgery in the form of localized excisions or combination therapies. Currently, more attention is paid to pediatric cases, so a study on adult incidences would provide a more holistic assessment of the cancer. Further investigation is needed to understand the effect of demographic/socioeconomic factors on rarity, earlier diagnosis, and treatment.
Concurrent chemoradiation and adjuvant chemotherapy in newly diagnosed glioblastoma multiforme: A retrospective analysis of single center.
Authors: Eluska Iruarrizaga, Estibaliz Iza, Joan Manel Mañe, Itziar Rubio, Eneko Novo, Lara Lombardero, María José De Miguel, Alberto Muñoz
Journal: Journal of Clinical Oncology (2023)

e14053 Background: The standard of care of glioblastoma multiforme (GBM) first line therapy is maximum safe debulking and posterior treatment based in concurrent chemo-radiation (Qt-Rt) followed by temozolomide-based chemotherapy. Despite a complete resection and adjuvant treatment, overall survival (OS) in patients (pts) with GBM is poor and it depends on tumor biology and patient characteristics. We analyzed retrospectively clinical and tumor biology characteristics of pts with GBM treated in our center with Qt-Rt +/- adjuvant Qt and their impact in OS. Methods: From November-2016 to October-2022, we collected data for 82 pts (median age: 60 years) who underwent Qt-Rt exclusively (25 patients) or Qt-Rt and adjuvant temozolomide (57 patients). Pts characteristics are detailed. Results: In multivariate analysis, significant difference of OS were observed in function of type of surgery (better OS in R0; p=0.015), performance status (better OS in PS 0-1; P=0.006), MGMT methylation (better OS in methylated; p=0.037), ATRX status (better OS in negative; p=0.05). No differences were founded in function of TERT (p=0.47) or p53 status (p=0.57). OS was significantly increased in pts treated with Qt-Rt and adjuvant Qt (17.7 +/- 1.7 months) vs Qt-Rt exclusively (11.35 +/-1.62 months) (p=0.013). After Qt-Rt treatment, radiological response was (%): no evidence of disease 13.4/partial response 6.1/stable disease 58.5/progressive disease 18.3/not evaluated 2.4. Most relevant adverse event G3/4 during Qt-Rt (%): thrombocytopenia 7.31, neutropenia 8, leukopenia 3.65, anemia 2.4, thrombosis 2.4. There were 2 toxic death (infection grade 5). After Qt-Rt, 57 pts received adjuvant treatment (median number of cycles: 5; range 1-15). Most relevant toxicity G3/4 during this therapy was (%): asthenia 3.05, anorexia 1.75, thrombocytopenia 5.26, neutropenia 3.05, leukopenia 1.75. There was 1 toxic death (infection G5). Pts that received 4 or more cycles of adjuvant temozolomide had a significant impact on OS versus those that completed 3 or less cycles (19.28 +/- 2 months vs. 12.05 +/- 1.5 months; p=0.022). Conclusions: Temozolomide-based chemotherapy in GBM is an effective and safe therapy and the premature interruption of this treatment may impact on OS. It is essential to know patient characteristics and tumor biology in order to identify patients that will beneficiate from this treatment.[Table: see text]
Integrating technology to support data management abstraction of adverse events (AE) and concomitant medications (ConMed) from the electronic health record (EHR) to sponsor electronic data capture (EDC) systems using design thinking (DT) methodology.
Authors: Leemor Yuravlivker, Michael T. Buckley, Nancy Bouvier, Sundar Jeevarathnam, Steve Lazan, Renata Panchal, Mairi McKellop, Joseph M. Lengfellner, Stephanie Lucia Terzulli, Paul Sabbatini
Journal: Journal of Clinical Oncology (2023)

e13624 Background: Manual abstraction of data from a site’s EHR to pharmaceutical sponsor’s EDC system is labor intensive and inefficient. To reduce the time and effort of this process for data managers (DM), a web-based application, Clinical Trials Data Hub (CTDH), was developed using Design Thinking methods. It extracts and consolidates AE and ConMed data from the EHR and displays it in a user friendly, automated, and consolidated view for easy entry into EDC forms. Methods: Following DT methodology to develop CTDH, we interviewed 12 DMs to identify data entry bottlenecks, and ideated solutions for what is now CTDH. To evaluate CTDH’s value, we built a functioning prototype using Splunk and conducted pilot A/B testing with 6 DMs for 2 use cases (Case I: basic easy to find ConMed linked to the AE, and Case 2: complex, where the ConMed linked to the AE was buried in a 33-page document) using their current workflow (A) versus CTDH (B) where a 5-minute training of CTDH occurred prior to testing. We hypothesized that CTDH would outperform current workflows across 3 primary outcomes: 1) correct data identification, 2) time to identify data, and 3) using a modified Single Ease Question (SEQ) rating scale to assess how difficult users found the task. This study was conducted in Jan-Aug 2022 at a large single-center cancer hospital. Results: DMs spend ~20 hours/week on data entry; the majority of which is spent searching the EHR for which ConMeds are associated with an AE. A/B testing results are noted in Table I (see below). Use case 2 showed that DMs using CTDH reduced the time to find one ConMed linked to an AE by 148%, saving ~5 minutes in one task. 5 of 6 participants preferred CTDH to existing clinical systems. Conclusions: Our findings suggest that CTDH allows DMs to 1) identify AE and ConMed data required for EDCs more quickly than in current workflow, 2) identify data more accurately to be entered in sponsor EDCs, and 3) perceive the task of identifying this data to be easier. CTDH reduces the time DMs spend searching clinical systems and documents and has the potential to save meaningful time per patient per study. CTHD will launch into production in May 2023. Digital tool product development using DT methodology has the potential to improve operational efficiency and the clinical staff user experience. This is particularly important in an industry that has struggled with burnout, cost containment, and high turnover. [Table: see text]
Vulnerability to immune therapy in BRAF- and MYB-altered pediatric gliomas.
Authors: Michael DeCuypere, Melissa LoPresti, Hinda Najem, Shashwat Tripathi, Joanne Xiu, Hilary Seifert, Valerie I. Brown, Giselle Y. López, Theodore Nicolaides, Craig M. Horbinski, Amy B. Heimberger
Journal: Journal of Clinical Oncology (2023)

2066 Background: The frequency and expression of predictive immune biomarkers in pediatric gliomas is relatively unknown. Here, we sought to define predictive signatures of immunotherapy responders by examining immune checkpoint expression, immune cell population signatures, and gene amplifications in a variety of pediatric gliomas. Methods: We profiled a cohort of pediatric, adolescent, and young adult glioma samples submitted to Caris Life Sciences (Phoenix, AZ) for analysis (N = 207). The cohort was further stratified by driver mutations: IDH mutant (N = 103), H3-3A mutant (N = 36), MYB-altered (N = 4), BRAF-altered (N = 39), and IDH wild type [IDH WT] (N = 25). De-identified next generation DNA sequencing (592-gene or whole exome) and RNA (whole transcriptome) sequencing were used to determine tumor-infiltrating immune cell signatures and immune checkpoint protein expression. Transcriptomic signatures predictive of response to immunotherapy (T cell inflamed score) and replication stress response defect (RSRD) score were calculated on transcripts per million (TPM) values. Immune cell fractions were estimated using RNA deconvolution (quanTIseq). Results: BRAF-altered tumors showed the highest IFN gamma signature (a clinically relevant inflammatory biomarker), a high pro-inflammatory M1 macrophage signature, and very high CD4+/CD8+ T cell signatures compared to other tumor groups. IDH mutant, but not WT gliomas, were relatively deficient in T cell infiltration but revealed an increase in dendritic cell signatures. IDH WT gliomas showed more T cell enrichment but higher immune suppressive checkpoint expression. H3-3A mutant tumors showed relatively low immune cell infiltration and immune checkpoint expression. Pro-inflammatory M1 macrophages were lower in the high-grade glioma microenvironment compared to low-grade. Immune suppressive M2 macrophages were elevated in the IDH WT microenvironment relative to other gliomas. There was no apparent difference in the frequency of PD-1+ T cells and tumor-expressed PD-L1 among the various molecularly defined pediatric glioma groups. Conclusions: In general, BRAF- and MYB-altered gliomas displayed high immune activation relative to other tumors. IDH WT tumors have an immune suppressive microenvironment with relatively high immune checkpoint expression. Based on predictive markers, BRAF- and MYB-driven gliomas show signatures suggesting the possibility of a greater response to immunotherapies than IDH WT/mutant gliomas or H3-3A gliomas.
Engineering of mesenchymal stem cells to express cytosine deaminase gene with a selecable marker gene.
Authors: Haeyoung Suh-Kim, Min-Gyeong Kim, Young-jun Lee, Narayan Bashyal, Sung-Soo Kim, Da-Young Chang
Journal: Journal of Clinical Oncology (2023)

e14050 Background: Suicide genes induce apoptosis not only in the cell itself but also in surrounding cells. The former is called the suicide effect and the latter is called the bystander effect. Two major suicide gene strategies currently pursued, cytosine deaminase (CD)/5-fluorocytosine (5-FC) and the herpes simplex virus-thymidine kinase/ganciclovir. Both genes have similar potential to induce suicide effects, but bystander effect is higher in CD/5-FC. Here we show that the level of CD expression/activity influence the anti-cancer activity of CD-expressing cells and further demonstrate the need to use selectable markers during manufacturing of CD-expressing cells. Finally we test whether live microbes harboring the shed selectable marker genes are controllable by commonly used antibiotics. Methods: We introduced a microbial CD gene and puromycin-N-acetyltransferase ( pac) gene to bone-marrow derived mesenchymal stem cells MSCs) using a retroviral vector and selected the transduced cells with 4 ug/mL puromycin for one week. To determine the effect of purity, we varied the ratio of CD-expressing MSCs with naïve MSCs and 5-FC concentration in the culture and on co-cultured glioma cells. To mimic the situation in which the shed pac gene is transmitted to live microbes in vivo, we introduced the pac gene to E. coli and tested the growth of the pac-expressing E. coli using VITEK following the standard protocol M100-S32 in the presence of diverse antibiotics. Results: We found that selection of CD-expressing cells with puromycin during manufacturing process enhanced the bystander (anti-cancer effect). Lowering the purity of CD-expressing MSCs required more 5-FC with higher IC50. Growth of pac-expressing E. coli was completely inhibited by commonly used antibiotics in the hospital. Conclusions: We proved that antibiotic selection is necessary during manufacturing process. We also showed that the risk of transmission of shed pac gene can be manageable with commonly used antibiotics. We propose that using pac selectable marker gene can be beneficial to maintain the purity of engineered cells.